RT Journal Article
SR Electronic
T1 Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in perfused rat livers
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.084624
DO 10.1124/dmd.118.084624
A1 Bonnaventure, Pierre
A1 Cusin, Fabien
A1 Pastor, Catherine M
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/01/25/dmd.118.084624.abstract
AB In the liver, several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. These approaches include in vitro assays and pharmacokinetic models that predict how inhibitors modify the systemic and liver concentrations of the victim drugs. Imaging is another approach that shows how inhibitors might alter liver concentrations stronger than systemic concentrations. In perfused rat livers associated with a gamma counter that measures continuously liver concentrations, we previously showed how fluxes across transporters generate the hepatocyte concentrations of two clinical imaging compounds, one with a low extraction ratio (Gadobenate dimeglumine, BOPTA) and one with a high extraction ratio (Mebrofenin, MEB). BOPTA and MEB are transported by rat Oatps and Mrp2 which are both inhibited by rifampicin. The aim of the study is to measure how rifampicin modifies the hepatocyte concentrations and membrane clearances of BOPTA and MEB and to determine whether these compounds might be used to investigate transporter-mediated drug-drug interactions in clinical studies. We show that rifampicin co-perfusion greatly decreases BOPTA hepatocyte concentrations, but increases those of MEB. Rifampicin decreases strongly BOPTA hepatic clearance. In contrast, rifampicin decreases moderately MEB hepatic clearance and blocks the biliary intrinsic clearance, increasing MEB hepatocyte concentrations. In conclusion, low concentrations prevent the quantification of BOPTA biliary intrinsic clearance, while MEB is a promising imaging probe substrate to evidence transporter-mediated drug-drug interactions when inhibitors act on influx and efflux transporters.